1. Field of the Invention
The present invention relates to a liquid composition suitable for ejecting a liquid containing at least one kind of insulins and to a method of ejecting the liquid.
2. Related Background Art
Currently, many attempts have been conducted to utilize a protein solution as liquid droplets. Examples thereof include transmucosal administration for the drug delivery method or an application of liquid droplets forming technique using the protein solution to a biochip or biosensor in which an extremely small amount of a protein is required. In addition, attentions have been paid on a method of using microdroplets of protein for control on crystallization of protein and also for screening of a physiologically active substance (see, for example, Japanese Patent Application Laid-Open No. 2002-355025, Allain L R et al., “Fresenius J. Anal. Chem.”, vol. 371, p. 146-150, 2001, and Howard E I and Cachau R E, “Biotechniques”, vol. 33, p. 1302-1306, 2002).
In recent years, mass production of proteins, particularly of useful proteins such as enzymes and those having physiological activities has become possible by any technology such as genetic recombinant technology. Therefore, the process of making protein into liquid droplets can be a useful means in the field of searching, utilizing, and applying a novel protein medicine. More specifically, there are increasing significant demands on means for providing patients with various pharmaceutical agents by microdroplets. In particular, microdroplets have become important means for the administration of proteins, peptides, and other biological materials from the lungs. In other words, pulmonary administration has been remarked as an administration route in place of an injection of a macromolecule peptide-based drug represented by insulin because the lungs have air vesicles with their own extensive surface areas of 50 to 140 m2 and the epithelium provided as a barrier of absorption is as thin as 0.1 μm, while the enzyme activities of the lungs are smaller than those of the gastrointestinal tract.
Among the macromolecular peptide drugs which can be administered through the lungs, much attention has been paid on insulins. The patient with type I diabetes cannot produce insulin in the body and requires the administration of insulins before a meal. Examples of the insulins include normal insulins, rapidly-acting insulin aspart, insulin lispro, long-acting insulin glargine, and insulin detemir. The administration of insulins by injection before every meal may result in pain and infection, so the pulmonary administration of insulins without such concerns has attracted attention.
In general, the deposition of microdroplets of drug in the lungs has been known to depend largely on the aerodynamic particle sizes thereof. In particular, the delivery of the microdroplets to the air vesicles in the deep portions of the lungs requires an administration with high reproducibility for the liquid droplets having particle sizes of 1 to 5 μm and having a narrow particle size distribution.
As a method of preparing liquid droplets with a narrow particle size distribution, the use of a droplet generator diverted from those used in inkjet printing based on the principle of a liquid ejection in the production of extremely fine liquid droplets and the application of the liquid droplets have been reported in the art (see, for example, U.S. Pat. No. 5,894,841 and Japanese Patent Application Laid-Open No. 2002-248171). Here, the liquid ejection by the specific inkjet system concerned involves leading a liquid to be ejected into a small chamber where the liquid is subjected to a physical stress, thereby allowing liquid droplets of the liquid to be ejected from orifices. An ejecting method may be any one of those known in the art, such as a method that involves generating air bubbles spouting liquid droplets through orifices (ejection opening) formed on a chamber by means of an electrothermal conversion element such as a thin-film resistor (i.e., a thermal inkjet system) and a method that involves ejection liquid directly from orifices formed on a chamber by means of a piezoelectric transducer (i.e., a piezo inkjet method).
For allowing the lungs to absorb a drug, in particular, in a case of insulins, for example, the dose of the drug should be controlled precisely. Therefore, making liquid droplets based on the principle of the inkjet system, which is capable of adjusting the ejection amount thereof, is a very preferable configuration. However, the ejection of a solution should be surely carried out in this case, the ejection of the solution of insulins is unstable when the solution is only controlled with respect to its surface tension and viscosity. Therefore, there has often been difficulty in ejection with high reproducibility and high efficiency.
A problem accompanying the formation of liquid droplets from an insulins solution based on the principle of the inkjet system is to make the structure of insulins unstable by physical force, such as pressure or shearing force, to be applied when the liquid droplets are ejected or by high surface energy which is characteristic of fine liquid droplets. In addition to this, when a thermal inkjet system is used, thermal energy is also added. The conformation of insulins are fragile. Thus, when the conformation is destroyed, the aggregation and degradation of insulins may be caused and affect the normal ejection. The physical actions are extremely larger than the shearing force and thermal energy to be applied by conventional stirring or heat treatment (for example, in the case of the thermal inkjet system, approximately 300° C. and 90 atm are applied momentarily). In addition, several physical stresses are impressed at the same time, so the stability of the insulins may tend to be substantially lowered, compared with the case of usually handling the insulins. If such a problem occurs, the insulins may be aggregated at the time of making liquid droplets and nozzles may be then clogged, thereby making it difficult to eject liquid droplets.
Further, liquid droplets having diameters of 1 to 5 μm, which are suitable for the inhalation into the lungs, are extremely much smaller than those having diameters of approximately 16 μm generally used in any printer commercially available at present. Therefore, a larger surface energy or shearing stress may be impressed on the liquid droplets than on the liquid droplets used in the printer. Therefore, it is much more difficult to eject microdroplets suitable for inhalation of the insulins into the lungs.
In addition, the present inventors have studied and found out that the insulins solution can be unstably ejected as the drive frequency of a thermal inkjet head increases. This is because part of the insulins can be insoluble in water when the liquid to be ejected is heated by a heater in the thermal inkjet head and the heater can be prevented from transferring energy to the liquid. When the drive frequency is low, even though an insoluble matter is temporarily generated, it can be re-dissolved within a time period before the next driving. On the other hand, when the drive frequency increases, the stability of ejection may decrease due to insufficient recovery from the dissolution. However, a low drive frequency leads to a decrease in amount of the liquid which can be ejected per unit time, so the ejection should be carried out at an adequately high frequency in actual use.
Therefore, it is essential to develop an ejection liquid that allows a stable ejection of insulins in actual use.
In contrast, as a method of stabilizing insulins, a method of adding a surfactant, glycerol, any of various kinds of carbohydrates, a water-soluble polymer such as polyethylene glycol, or albumin has been known in the art. However an improvement in ejection stability when insulins are ejected on the basis of a thermal inkjet system is hardly attained or is not attained.
In addition, there is substantially no effect on an improvement in ejection performance when a solution of insulins is ejected even after formulation with polyols such as ethylene glycol and glycerin, and a moisturizing agent such as urea, which are suitable additives for ink to be used in inkjet printing.
For the liquid composition of insulins for use in pulmonary inhalation of liquid droplets produced by using the thermal inkjet system, there have been known liquid compositions which contain compounds for controlling surface tension and humectants (see International Publication No. WO 02/094342). In this case, a surfactant and a water-soluble polymer such as polyethylene glycol are added to improve the stability of a protein and a peptide as shown an insulin in a solution formed into liquid droplets by modifying the surface tension, viscosity, and moisturizing activity of the solution.
However, no detailed description about ejection stability is given in the International Publication No. WO 02/094342. Further, according to the investigation of the present inventors, it has been found that the effect of the addition of a surfactant and a water-soluble polymer is insufficient when the concentrations of the protein and the peptide are high. Further, it has also been found that most of the surfactants have no effect, and that the ejection stability of a protein solution is not determined by its surface tension, viscosity, and moisturizing action. In other words, the aforementioned method is not a general method of stabilizing the ejection when insulins are ejected by the thermal inkjet system.